An Efficient Procedure for the Direct Nucleophilic Substitution of the Abiko-Masamune Auxiliary

Abstract

An efficient method for the nucleophilic displace-ment of the Abiko-Masamune auxiliary is reported, which involves i-PrMgCl for intermediate ester activation.

synthetic methodology - Lewis acid - ester cleavage - ­aldol reaction - Abiko-Masamune auxiliary

References and Notes

1a Abiko A. Liu J.-F. Masamune S. J. Am. Chem. Soc.  1997,  119:  2586 

1b Liu J.-F. Abiko A. Pei Z. Buske DC. Masamune S. Tetrahedron Lett.  1998,  39:  1873 

1c Inoue T. Liu J.-F. Buske DC. Abiko A. J. Org. Chem.  2002,  67:  5250 

For recent reviews on the aldol reaction and direct methods for polypropionate synthesis, see:

2a Brodmann R. Lorenz M. Schäckel R. Simsek S. Kalesse M. Synlett  2009,  174 

2b Li J. Menche D. Synthesis  2009,  2293 

For selected recent examples, see:

3a Evano G. Schaus JV. Panek JS. Org. Lett.  2004,  6:  525 

3b Smith AB. Simov V. Org. Lett.  2006,  8:  3315 

3c White JD. Smits H. Org. Lett.  2005,  7:  235 

3d Menche D. Hassfeld J. Li J. Rudolph S. J. Am. Chem. Soc.  2007,  129:  6100 

3e Jin J. Chen Y. Li Y. Wu J. Dai W. Org. Lett.  2007,  9:  2585 

3f Ying Y. Hong J. Tetrahedron Lett.  2007,  48:  8104 

4a Fanjul S. Hulme AN. White JW. Org. Lett.  2006,  8:  4219 

4b Fanjul S. Hulme AN. J. Org. Chem.  2008,  73:  9788 

5

Experimental Procedure
To a cold solution (-78 ˚C) of dimethyl methylphosphonate (156 mL, 2.93 mmol, 11 equiv) in THF (1 mL) were added KHMDS (0.5 M in toluene, 2.66 mL, 1.33 mmol, 10 equiv), and the resulting suspension was stirred at -20 ˚C for 2 h. To a cold solution (-78 ˚C) of the ester (92.1 mg, 0.136 mmol, 1.0 equiv) in THF (1 mL) was added i-PrMgCl (2.0 M in Et₂O, 204 µL, 0.409 mmol, 3.0 equiv). After 20 min the above mixture was added via cannula. The reaction mixture was warmed to -20 ˚C during 1.5 h and stirred at -20 ˚C for 30 min. Sat. aq NH₄Cl (6 mL) and H₂O (6 mL) were added, the organic phase separated, and the aqueous phase thoroughly extracted with EtOAc (4 × 6 mL). The combined organic phases were dried over MgSO₄ and concentrated under reduced pressure. Silica gel chromatography (hexanes-EtOAc = 1:2) afforded the phosphonate 6a (40.9 mg, 0.109 µmol, 80%) as a colorless oil and the chiral Masamune alcohol auxiliary as a white solid (50.6 mg, 0.120 mmol, 88%).

6

All new compounds had spectroscopic data in support of the assigned structures. Sample data follow.
Compound 6a: ^¹H NMR (300 MHz, CDCl₃): δ = 0.93 (d, J = 7.0 Hz, 3 H), 1.82 (s, 3 H), 3.06 (dq, J = 9.2, 7.0 Hz, 1 H), 3.17 (dd, J = 18.7, 13.8 Hz, 1 H), 3.25 (dd, J = 18.7, 13.8 Hz, 1 H), 3.76 (s, 3 H), 3.80 (s, 3 H), 4.25 (d, J = 9.2 Hz, 1 H), 6.30 (s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.7, 18.7, 41.2, 42.9, 50.2, 53.2, 53.3, 79.2, 80.9, 147.4, 205.4, 205.5. HRMS: m/z calcd for C₁₀H₁₈IO₅PNa [M + Na]⁺: 398.9834; found: 398.9836.
Compound 8: ^¹H NMR (400 MHz, CDCl₃): δ = 1.09 (d, J = 7.1 Hz, 3 H), 1.81 (d, J = 1.0 Hz, 3 H), 3.15 (m, 1 H), 3.17 (s, 3 H), 3.58 (d, J = 6.1 Hz, 1 H), 3.69 (s, 3 H), 4.26 (t, J = 6.4 Hz, 1 H), 6.30 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 15.1, 20.1, 32.2, 38.2, 61.8, 79.0, 80.1, 148.1, 176.3. HRMS: m/z calcd for C₉H₁₆INO₃Na [M + Na]⁺: 336.0073; found: 336.0075.
Compound 17: ^¹H NMR (400 MHz, CDCl₃): δ = 0.06 (s, 6 H), 0.90 (s, 9 H), 1.11 (d, J = 7.1 Hz, 3 H), 1.82 (s, 3 H), 2.94 (dq, J = 7.0, 7.1 Hz, 1 H), 3.04 (d, J = 5.6 Hz, 1 H), 3.20 (s, 3 H), 3.68 (s, 3 H), 4.24 (d, J = 5.1 Hz, 2 H), 4.60 (ddd, J = 9.2, 7.0, 5.6 Hz, 1 H), 5.43 (d, J = 9.2 Hz, 1 H), 5.75 (dt, J = 15.3, 5.1 Hz, 1 H), 6.24 (d, J = 15.3 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = -5.1, 13.2, 14.4, 18.5, 26.0, 41.5, 61.5, 63.8, 70.7, 128.7, 131.8, 133.7, 136.0, 189.2. HRMS: m/z calcd for C₁₈H₃₅NO₄SiNa [M + Na]⁺: 380.2233; found: 380.2232.

7

Using metalated ethyl congener of 5, i.e., diethyl ethylphosphonate, resulted in only low conversion under identical reaction conditions.

8

Experimental Procedure
To a solution of ester 4 (231 mg, 0.342 mmol, 1.0 equiv) in THF (1 mL) was added i-PrMgCl (ca. 2 M in THF, 0.17 mL, 0.34 mmol, 1.0 equiv), after 10 min a suspension of magnesium chloride methoxy(methyl)amide complex, which was prepared by addition of i-PrMgCl (ca. 2 M in THF, 3.42 mL, 6.84 mmol, 20 equiv) to a suspension of N,O-dimethylhydroxylamine hydrochloride (334 mg, 3.42 mmol, 10 equiv) in THF (3 mL) at -20 ˚C, was added. The reaction mixture was stirred at -20 ˚C for 2 h and warmed up to -10 ˚C (1 h). The reaction was quenched by addition of sat. aq NH₄Cl (5 mL). The product amide was extracted into EtOAc (3 × 20 mL), and the combined organic layers were dried over MgSO₄ and concentrated in vacuo. After flash chromatography (hexanes-EtOAc = 2:1 to 1:1) amide 8 (77.0 mg, 0.246 mmol, 72%) was obtained as a white solid.

9

The corresponding dienes of 9 and 12 were obtained in 38% and 6% yield, respectively.

10 Menche D. Arikan F. Perlova O. Horstmann N. Ahlbrecht W. Wenzel SC. Jansen R. Irschik H. Müller R. J. Am. Chem. Soc.  2008,  129:  14234 

11 Famer LJ. Marron KS. Koch SSC. Hwang CK. Kallel EA. Zhi L. Nadzan AM. Robertson DW. Bennani YL. Bioorg. Med. Chem. Lett.  2006,  16:  2352 

12

Experimental Procedure
To a flask containing Ph₃PCHCHO (146 mg, 0.481 mmol, 1.0 equiv) was added a solution of 15 (207 µL, 1.52 mmol, 3.0 equiv) in dry CH₂Cl₂ (100 µL). The reaction mixture was stirred for 15 h at r.t. and purified direct by flash chromatog-raphy (hexanes-Et₂O = 6:1 to 1:1) to give aldehyde 14 (64.6 mg, 0.384 mmol, 80%) as colorless crystals.